DIFFERENTIAL-EFFECTS OF GLUT-1 OR GLUT-4 OVEREXPRESSION ON INSULIN RESPONSIVENESS IN TRANSGENIC MICE

The effect of glucose transporter expression on insulin-stimulated who le body glucose disposal was examined in transgenic mice overexpressin g GLUT-1 or GLUT-4. Transgenic mice and their control littermates were subjected to a euglycemic hyperinsulinemic clamp under pentobarbital sodium anesthesia using an insulin infusion rate of 20 mU.kg(-1).min(- 1) and a variable glucose infusion rate (GIR). Fasted mice overexpress ing GLUT-1 in skeletal muscle exhibited a GIR that was only 54% that o f controls (19.3 +/- 1.8 vs. 36.0 +/- 3.9 mg.kg(-1).min(-1)) when bloo d glucose was clamped at euglycemic values. In contrast, fasted mice o verexpressing GLUT-4 in fat and muscle exhibited a GIR that was 40% hi gher than controls (53.9 +/- 2.3 vs. 39.1 +/- 2.5 mg.kg(-1).min(-1)). At the end of the clamp, beta-hydroxybutyrate levels were 1.0-fold hig her in the GLUT-1 transgenic mice relative to nontransgenic littermate s (2.0 +/- 0.6 vs. 0.2 +/- 0.1 mM) but did not differ between the GLUT -4 transgenic mice and their control littermates (0.3 +/- 0.1 vs. 0.3 +/- 0.1 mM). These data demonstrate that the level of expression of a glucose transporter in muscle and fat can have marked effects on whole body glucose homeostasis and fuel metabolism. Insulin responsiveness was enhanced by overexpression of GLUT-4. Strikingly, however, overexp ression of GLUT-1 in muscle induced a profound reduction in insulin-st imulated whole body glucose disposal. The effect of transporter overex pression appears to be isoform specific, although some of the differen ce in the effects of the GLUT-1 and GLUT-4 transgenes may be due to di fferences in the level of overexpression or the tissue distribution.